Thirty-two of 37 countries (86%) were included in the study. Vignettes for each of these were created . The five non-respondent countries excluded from the study were: Australia, Croatia, Cyprus, Luxembourg, and Wales. Responses were provided by 33 country experts (two experts for the different jurisdictions in Canada) (Figure 1). Eighty percent of experts work within, or close to, HTA/reimbursement processes in the public sector, with the remaining being from academia, health care providers or private sector. Their positions are directorship-level involved in the pricing and reimbursement processes (45%), HTA scientific experts (30%), appraisal committee members (6%), academics or clinical experts (18%), or consultants (3%).
The next section provides an overview of the countries with supplemental processes, explores their key features according to the typology, and examines countries without RDT supplemental processes.
Supplemental processes for rare disease treatments
Forty one percent (13/32) of countries include supplemental processes specifically targeting rare and/or ultra-RDTs (Figure 2). Integration levels of these supplemental processes within standard processes were categorised as low, medium and high. Processes with low integration are either completely (2/15) or partially separate (2/15) from the standard process. The main distinction between separate supplemental and standard processes are the different evidence submission requirements and appraisal committees. This is the case for the HST programme in England and the ultra-RDTs pathway in Lithuania, both targeting ultra-RDTs. They also include different features intended to better adapt to the specificities of RDTs. Both recognise the challenges for evidence generation and tend to be more lenient with its interpretation. The HST programme in England has an explicit decision-making framework that allows for broader consideration of treatment value (nature of the condition, clinical effectiveness, value for money, impact beyond direct health benefits) and greater WTP, whereas the ultra-RDT pathway in Lithuania has different appraisal rules (therapeutic value not graded), a special reimbursement list with no waiting list, and special pricing rules.
Partially integrated supplemental processes include the ultra-RDT pathway in Scotland (where the wider decision-making framework implemented in 2016 was changed to an ultra-RDT pathway in 2019) and the OMP pathway in Germany. In Scotland, once a product is designated as an ultra-RDT by the Scottish Medicines Consortium (SMC), it is submitted for initial assessment to SMC using a special submission form and it is then made available in Scotland for three years with a data collection plan and re-assessment after three years. In Germany, the assessment and appraisal are conducted by the Federal Joint Committee (G-BA) instead of the independent Institute for Quality and Efficiency in Health Care (IQWiG). RDTs are also subject to more simplified evidentiary requirements (e.g. no need for comparative data), and their additional benefit is considered automatically proven. There is also an option for conditional approval.
Countries were defined as having adapted processes for RDTs when they include adjustments to their standard process that allow better management of the challenges with RDTs. This is the case for Norway, Sweden and Slovakia, in which the adapted process targets ultra-RDTs, and in Scotland for OMPs. The main process features common to all the countries relate to a greater understanding of the challenges to produce high quality evidence for RDTs, and more favourable reimbursement through a higher WTP. Slovakia also includes an exemption from presenting an economic evaluation. In Scotland, being an OMP has been seen as a “modifier” to the appraisal process for many years, providing more flexibility in the decision-making process . Recently, there is also the possibility to hold a patient and clinician engagement (PACE) meeting for OMPs.
Five of the 13 countries with supplemental processes for RDTs have a high level of integration with standard processes. These are either expedited processes or processes where rarity is weighted. The three countries with expedited processes allow for an earlier start of the assessment process (and subsequently earlier access for patients to these treatments). The other two countries have points systems to determine reimbursement status (e.g. Romania) and WTP (e.g. Slovakia), where OMPs get extra points.
Two of the 13 countries with supplemental processes use alternative routes to reimburse subgroups of RDTs, through HTA exemptions. These include the separate state-reimbursement budget for children living with rare diseases in Latvia and a list of rare diseases for which medicines are automatically reimbursed in Bulgaria.
Distinction of rare versus ultra-rare disease treatments within supplemental processes
All processes with a medium to low level of integration within standard processes target ultra-RDTs, with the exception of the orphan medicines pathway in Germany and the Patient and Clinical Engagement (PACE) programme and SMC modifiers in Scotland intended for OMPs (Table 1). The ultra-RDT definitions are defined using prevalence criteria ranging from less than 1 in 50,000 (Scotland, Slovakia) to less than 1 in 200,000 patients (Lithuania, Bulgaria), or are not defined (Sweden, likely to be less than 1 or 2 in 200,000 patients). Additionally, most countries limit these special processes to ultra-RDTs with specific characteristics, such as treating a severe condition with high unmet need, to potentially effective and/or high cost treatments, requiring highly specialised management. Regarding the more integrated supplemental processes, eligible medicines are those with an OMP designation.
Key process features for appraisal of rare disease treatments
The distinctions between supplemental and standard processes have been characterised as features occurring throughout the HTA process, and are discussed in this section (Figure 3).
The countries with separate or partially separate processes have different clinical and/or economic evidence submission requirements. This is done through use of different submission forms as seen for the HST in England and ultra-RDT pathways in Lithuania and Scotland, or with the possibility of presenting a simplified version of the standard submission in Germany (exempt from presenting comparative data). In all other countries, evidentiary requirements are the same as for standard processes with the exception of Lithuania, Slovakia and Belgium, which don’t require economic models for ultra-RDTs.
The inclusion of disease-specific input is being achieved by involving patient and clinical experts in different ways across the HTA process, starting from the assessment phase. First, through the stand-alone PACE process in Scotland, where the SMC assessors discuss the added benefit of the treatment not captured within conventional clinical and cost-effectiveness assessments with those who have experience of the disease and/or treatment being assessed. This meeting can be requested by the manufacturer if a negative opinion is initially given by the assessment committee. A PACE statement is then drafted and becomes part of the evidence submitted to the appraisal committee. Second, the process may allow for patient and/or clinical experts to provide input about clinical issues. This is done in both countries with and without supplemental processes, and informs the assessment phase. Third, some countries have established committees with rare disease experts that support decision-making around pricing, reimbursement and use of the medicine. This is the case in Bulgaria with their rare disease expert committee that decides on inclusion of diseases on the special positive formulary (for which all treatments are reimbursed); in New Zealand with their clinical advisory committee; and in Ireland with their Rare Diseases Technology Review Committee enabling clinicians and other stakeholders to provide input in the post-HTA phase, and review MEA proposals.
Additionally, some processes may allow for an earlier start in the assessment process to guarantee more timely access to RDTs. This is seen in Belgium, Italy and New Zealand in their expedited processes targeting RDTs, which allow for the assessment process to start before marketing authorisation is granted.
The greatest number of features implemented in the supplemental processes relate to the appraisal phase. The main distinction seen within separate supplemental processes for ultra-RDTs is the existence of different appraisal committees, which provides a standing group with rare disease expertise who only assess RDTs. One of the main distinctions seen in England is in membership composition with the inclusion of rare disease clinical specialists (adult and paediatric), ethicists, geneticists, and expert centre representatives.
Broader consideration of value is another feature adopted in England’s and Scotland’s supplemental processes for ultra-RDTs (within their ultra-RDT decision frameworks), where context and specification of issues specific to rare diseases are considered as evidence. This is done by more detailed consideration about the nature of the condition (including consideration of severity, unmet need and existence of alternative treatments), and accounting for indirect costs and benefits on patients, carers and health system.
The most common feature in supplemental processes relates to allowing more leniency in the quality of the evidence. This is done through less stringent requirements for demonstrating added benefit (e.g. acceptance of non-comparative data), and/or willingness to accept surrogate endpoints or non-randomised controlled trials (RCTs). Generally, this is done on a case-by-case basis, if appropriate justification is provided or if the evidence is considered to be of best possible quality. Greater leniency may also be more acceptable for medicines with a high level of unmet need or those that have a high media profile.
In those countries where cost-effectiveness needs to be proven (e.g. where an economic submission is required), there may be more flexibility in the interpretation of the economic evidence. This is done by accepting natural outcome measures instead of QALYs or cost-consequence analyses, and including sensitivity analyses that reflect wider costs and benefits (Scotland) .
Some of the features included in supplemental processes allow for different decision rules. The first relates to different WTP, where a higher ICER than would be admissible in common conditions (Scotland, Norway, Sweden), or a higher adjusted WTP that increases with magnitude of benefit and QALY gained (England) would be accepted, or through a points-system calculation of the WTP threshold where OMPs get extra points (Slovakia). The second relates to alternative reimbursement rules, where the therapeutic benefit of the medicine would be considered proven (Germany), or would not be graded (Lithuania). In Romania, reimbursement status is based on a points system, where OMPs get extra default points. Third, the process features also include decision modifiers in the appraisal framework, which impact deliberation about WTP or reimbursement status. While most processes, including the standard ones, are mainly interested in severity, unmet need and existence of treatment alternatives, some of the processes explicitly account for rarity or other criteria that may favour appraisal of RDTs (e.g. children, equality or the innovative nature of treatment ). Rarity is accounted for in Scotland (as part of its decision modifiers) and Netherlands, where greater uncertainty or unfavourable cost-effectiveness may be more acceptable. Other criteria that may influence the decisions are equality (England, New Zealand, Netherland), children (Germany, Netherlands), ethical considerations (Netherlands, Slovenia, Bulgaria, Latvia, Finland), or innovative nature of treatment (England, Italy, Greece). These appraisal criteria are considered both in supplemental and standard processes.
Pricing and reimbursement
Many countries include different forms of conditional approval agreements or MEAs, aiming to collect additional data to facilitate later re-assessment of added benefit or cost-effectiveness. This is the case for England’s HST programme, Scotland’s ultra-RDT pathway, Germany, Norway, Slovakia, and Belgium.
A few countries also include alternative routes to pricing and reimbursement for a group of RDTs, where they would be exempt from HTA as a whole. This is the case in Bulgaria, where all medicines used to treat conditions included on a special list of rare diseases would be automatically reimbursed, and in Latvia, with their separate state-budget for children with rare diseases.
Impact and proposed changes
Country experts were asked to state the impacts of their supplemental processes for RDTs. Increased acceptance rate was the most common response, resulting in the reimbursement of medicines that otherwise would not be reimbursed. The assumption of proven added benefit was considered to ensure a stronger negotiating position for the manufacturer and more flexibility in pricing. Some countries stated that these processes are more adapted to dealing with specificities in appraisal of RDTs. These processes allow special approaches to be taken for reimbursement of RDTs with clinical and/or budgetary issues in a consistent way, rather than on a case-by-case basis, supporting fairness in the decision-making system.
Changes in four of the 13 countries with supplemental processes are also being discussed, including refinement of processes (Sweden), potential legislative changes (Romania), implementation of a separate budget for adult rare disease patients (Latvia) and establishment of a therapy monitoring process (Bulgaria).
What are countries with standard processes doing?
In total, 19 countries (out of 32) do not have supplemental processes targeting RDTs, but may have features enshrined within their processes that might facilitate appraisal of RDTs. The most common feature included is granting more leniency around quality of clinical evidence (Austria, Canada, France, Estonia, Hungary, Poland, Portugal, Czech Republic, and Netherlands). The other features included acceptance of non-local language evidence submissions in Estonia; inclusion of disease-specific experts to input into the assessment phase in several countries; greater flexibility in the interpretation of the economic model or different WTP in Estonia (if consideration of cost/QALY is recognised as not possible, price would be set similar to other ultra-RDTs); ability to implement conditional approvals (Austria, Canada, Ireland, Italy, Czech Republic, Netherlands); or separate budgets (separate fund for innovative and cancer medicines in Italy, specific funds for political solutions in Austria). Finally, as stated earlier, some countries include criteria in their value assessment frameworks that may favour RDTs.
Two countries have processes that may be applicable to RDTs. In the Czech Republic, highly innovative medicines are eligible for conditional reimbursement, and do not need to prove cost-effectiveness. In France, their expedited processes target medicines with high unmet need. In addition to the expedited process for OMPs, Italy includes innovativeness criteria in their standard process, for which those medicines considered fully innovative will be automatically included in the regional formulary as part of a conditional approval.
Eleven of the 19 countries without supplemental processes are engaged in ongoing discussions about implementing changes in their processes for RDTs. Discussions revolve around general process changes in the standard pathway, or process changes for orphan medicines, including implementing exemptions for economic models or including bespoke patient involvement processes.